Administration of many therapeutic agents rapidly induces adverse side effects, or events, including but not limited to fever, headache, nausea, vomiting, breathing difficulties and changes in blood pressure. These adverse events limit the amount of a drug or therapeutic compound that can be given, which in turn limits the therapeutic effectiveness that could be achieved with higher doses of the drug. There is a continuing need to develop techniques which limit the toxicity of higher drug doses so that therapeutic efficacy can be improved. This need exists for both polypeptide and non-polypeptide compounds.
Antibodies are one type of polypeptide compound for which there are frequently adverse events upon administration which limit the dose of the compound that can be administered. One compound associated with adverse side effects is the murine monoclonal antibody OKT3. OKT3 binds to the CD3 protein complex that is associated with the T cell receptor (TCR) found on the surface of all T lymphocytes. Administration of OKT3 to humans rapidly reduces the number of circulating T cells (e.g. OKT3 is a cell depleting compound) and reduces the amount of cell surface TCR found on those T cells that remain (Cosimi, et al., 1981 N Engl J  Med, 305(6), 308-314). The immunosuppressive effects of OKT3 have been therapeutically useful in the treatment of renal transplant rejection (Goldstein & Group, 1985 M Engl J Med, 313(6), 337-342). However, administration of OKT3 induces a number of adverse side effects, including fever, chills, nausea, vomiting and tightness of chest. These side effects are believed to be caused by cytokine release from T cells due to OKT3-induced activation (Abramowicz, et al., 1989 Transplantation, 47(4), 606-608) and complement activation (Raasveld, et al., 1993 Kidney International, 43, 1140-1149).
Several strategies have been developed to reduce the OKT3-induced side effects. Anti-inflammatory steroids have been shown to attenuate the OKT3-induced cytokine release (Goldman, et al., 1989 Lancet, ii (8666), 802) (Chatenoud, et al., 1990 Transplantation, 49(4), 697-702), and indomethacin can reduce the febrile response (First, Schroeder, Hariharan, Alexander, & Weiskittel, 1992 Transplantation, 53 (1), 91-94). A standard 5 mg dose of OKT3 administered as a 2 hour infusion instead of the usual bolus injection was better tolerated and reduced complement activation, but not the cytokine release (ten Berge, Buysmann, van Diepen, Surachno, & Hack, 1996 Transplant Proc. 28 (6), 3217-3220). The adverse events induced by OKT3 are most significant after the first dose. While the initial dose (typically 5 mg) induces cytokine release and activates complement, it also eliminates the target T cells. With fewer T cells and reduced TCR density on those that do remain, subsequent doses of OKT3 induce less cytokine release (Chatenoud, et al., 1989 N Engl J Med, 320 (21), 1420-1421). One group found that after four daily doses of 5 mg, dosing could safely be escalated to 10, 15, and 25 mg over the next 3 days (Woodle, et al., 1996 Clin Transplantation, 10, 389-395).
Adverse events have also been associated with the initial administration of monoclonal antibodies directed to other cell surface molecules. A humanized anti-CD4 monoclonal antibody induced fever, chills, hypotension and chest tightness when given intravenously to psoriasis and rheumatoid arthritis patients (Isaacs, et al., 1997 Clin Exp Immunol, 110, 158-166). This treatment down-modulated expression of CD4 and caused a reduction in the number of circulating CD4-positive T cells, and but was not completely depleting. Bispecific antibodies that interact with the CD64 molecule, a receptor for the constant region of immunoglobulin (Fc gamma R1), and tumor associated molecules (epidermal growth factor receptor MDX-447, or HER2/neu MDX-H210) were shown to cause flu-like symptoms such as fever and chills after the first dose (Curnow, 1997, Cancer Immunol Immunother, 45, 210-215). Similar to the effect of OKT3 on T cells, these antibodies caused a decrease in the number of circulating monocytes, which express CD64, and stimulated increases in plasma cytokines. A single dose of another monoclonal antibody directed to CD64 (MDX-33) down-modulated the expression of CD64 on monocytes and also caused chills, low-grade fever, headache and muscle aches.
The interaction of T-lymphocytes with antigen-presenting cells (APCs) is one of the initial steps in the activation of an immunological response to what is perceived by the immune system to be a foreign antigen. Although much attention has been focused on the primary interaction of the T-cell receptor with the MHC-antigen on the APC, several other cell surface components are also involved in T-cell activation. These ligand pairs located on the cell surface of the T-cell and the APC include: LFA-1/ICAM-1 (also ICAM-2 and ICAM-3), CD28/B7, CD2/LFA-3, CD4/MHC Class II, and CD8/MHC Class I. Interfering with the binding of any of these ligand pairs (e.g., with the use of binding molecules such as monoclonal antibodies) may decrease, inhibit, or discontinue the T-cell responses (de Fourgerolles et al., 1994, J. Exp. Med., 179:619-29; Dustin, M L et al, 1986, J Immunol, 137:245-54).
LFA-1 (consisting of CD11a and CD18 subunits) interaction with ICAM is necessary for T-cell killing, T-helper and B-cell responses, natural killing, and antibody-dependent cytotoxicity. In addition, LFA-1/ICAM interactions are involved in adherence of leukocytes to endothelial cells, fibroblasts, and epithelial cells, facilitating the migration of leukocytes from the vasculature to the sites of inflammation (Collins, T., 1995, Science and Medicine, 28-37; Dustin, M L. et al., 1991, Annual Rev Immunology, 9:27-66).
Using antibodies that interfere with LFA-1/ICAM interactions decreases or inhibits the inflammatory process by blocking the activation of T-cells and/or the extravasation of leukocytes. In vitro, monoclonal antibodies against LFA-1 or its ligands have inhibited T-cell activation (Kuypers, T. and Roos, D., 1989, Research in Immunology, 140:461-86; Springer, T A, 1987, Annual Rev Immunology, 5:223-52), T-cell dependent B-cell proliferation (Fischer, A. et al., 1986, J Immunol, 136:3198-203), target cell lysis (Krensky, A. et al., 1983, J Immunol, 131:6711-6), and adhesion of T-cells to vascular endothelium (Dustin, M L. et al., 1988, Journal of Cell Biology, 107:321-31). In mice, anti-CD11a antibodies have induced tolerance to protein antigens (Benjamin, R. et al, 1988, European Journal of Immunology, 18:1079-88; Tanaka, Y. et al., 1995, European Journal of Immunology, 25:1555-8), delayed the onset and reduced the severity of experimental autoimmune encephalomyelitis (Gordon, E J et al., 1995, Journal of Neuroimmunology, 62:153-60), inhibited lupus-associated autoantibody production, and prolonged survival of several types of tissue grafts (Cavazzana-Calco M S, Sarnacki S, Haddad E, et al., Transplantation 1995;59(11):1576-82; Nakakura E K, McCabe S M, Zheng B, Shorthouse R A, et al., Transplantation 1993;55(2):412-7; Connolly M K, Kitchens E A, Chan B, et al, Clinical Immunology and Immunopathology 1994;72(2):198-203; He Y, Mellon J, Apte R, Niederkorn J., Investigative Ophthalmology and Visual Science 1994;35(8):3218-25; Isobe M, Yagita H, Okumura K, Ihara A., Science 1992;255:1125-7; Kato Y, Yamataka A, Yagita H, et al., Ann Surg 1996;223(1):94-100; Nishihara M, Gotoh M, Fukuzaki T, et al., Transplantation Proceedings 1995;27(1):372; Talento A, Nguyen M, Blake T, et al, Transplantation 1993;55(2):418-22; van Dijken P J, Ghayur T, Mauch P, et al., Transplantation 1990;49(5):882-6). In human clinical studies, murine anti-CD11a monoclonal antibodies have been shown to help prevent graft failure following bone marrow transplantation (Cavazzana-Calco M S, Bordigoni P, Michel G, et al., British Journal of Haematology 1996;93:131-8; Fischer A, Friedrich W, Fasth A., Blood 1991;77(2):249-56; Stoppa A M, Maraninchi D, Blaise D, Viens P, et al, Transplant International 1991;4:3-7) and renal transplantation (Hourmant M, Le Mauff B, Le Meur Y, et al., Transplantation 1994;58(3):377-80; Hourmant M, Bedrossian J, Durand D, et al., Transplantation 1996;62(11):1565-70; Le Mauff B, Hourmant M, Rougier J P, et al., Transplantation 1991;52(2):291-6). An immunosuppressive drug that could reduce the incidence of both acute graft rejection and delayed graft function, while promoting long-term survival with minimum toxicity with the potential of tolerance induction would provide major benefits to the field of renal transplantation.
A need continues to exist for new methods of administering therapeutic compounds which reduces side effects and which increases the effectiveness of the therapeutic compound.